Replacement of ganglion cells through regeneration - structural and functional analysis of cell integration
Final Report Abstract
Mammals lack an endogenous repair mechanism after neuronal damage. Several groups around the world explore the possibilities of neuronal replacement to restore function in various parts of the CNS. Recent work on human embryonic stem cell derived tissue engineering of retinal neurons and successes in retinal cell transplantation are one major approach towards development of retinal repair strategies. Research on retinal regeneration and its limitations in mammals has the potential to contribute new insight towards basic understanding of retinal development, retinal cell engineering and it may offer a retinal repair strategy of its own. In injured retina of amphibian, fish and chicken Müller glia re-enter the cell cycle, dedifferentiate into a progenitor like cell and regenerate retinal neurons. Therefore, in my postdoctoral work I asked the question whether Müller glia in adult mice have a residual capacity to regenerate lost neurons in vivo. First we eliminated retinal ganglion and amacrine cells with intraocular neurotoxin (NMDA) injections and stimulated Müller glial to re-enter the mitotic cycle by treatment with mitotic growth factors. The proliferating Müller glia dedifferentiate and a subset of these cells differentiated into amacrine cells, as defined by the expression of amacrine cell-specific markers Calretinin, NeuN, Prox1, and GAD67-GFP. These results show for the first time that the mammalian retina has the potential to regenerate inner retinal neurons in vivo. Exposure to bright light damages photoreceptors and subsequent injection of growth factors did not increase the number of regenerated GAD67-GFP neurons compared to growth factor injections alone. This suggests that Müller glia can be stimulated to regenerate some amacrines independent of the mode of damage. However amacrine loss stimulates its regeneration significantly. Interestingly neither loss of ganglion, amacrine or photoreceptors followed by various treatments induced regeneration of bipolar cells. Whether the adult mouse retina cannot regenerate bipolar or only lost cell types are regenerated is unsolved. Thus, Müller glia can be induced to proliferate, dedifferentiate and regenerate retinal neurons, most likely amacrine cells, in the mouse retina. Loss of retinal interneurons, but not photoreceptors increases the number of regenerating interneurons significantly. Although more limited than chicken or fish retina, the adult mouse retina has the potential to regenerate inner retinal neurons after damage. In future research it will be very interesting to reveal the molecular pathways for neuronal regeneration and its differences to embryonic development, to identify roadblocks limiting mammalian regeneration and to develop strategies to enable complete endogenous regeneration. http://www.arvo.org/EWEB/dynamicpage.aspx?site=foundation&webcode=iora09grants http://www.eurekalert.org/pub_releases/2008-11/uow-mcb112408.php http://www.technologyreview.com/biomedicine/21713/ http://www.expert-reviews.com/doi/abs/10.1586/17469899.4.1.11 http://content.nejm.org/cgi/reprint/356/15/1577.pdf
Publications
- Efficient generation of retinal progenitor cells from human embryonic stem cells. Proc Natl Acad Sci U S A. 2006 Aug 22;103(34):12769-74
Lamba DA, Karl MO, Ware CB, Reh TA
- (2008) Müller Glia Cell derived Neural Regeneration in the Murine Retina. Program No. 703.3. Society for Neuroscience. Washington, DC
Karl M.O., Hayes S, Nelson B.R., Buckingham B. and Reh T.A.
- (2008) Müller Glia Cell Proliferation after Neurotoxic Injury in the Murine Retina. ARVO. IOVS. 49: E-Abstract 3550
Karl M.O., Hayes S, Nelson B.R., Reh T.A.
- Baf60c is a component of the neural progenitor-specific BAF complex in developing retina. Dev Dyn. 2008 Oct;237(10):3016-23
Lamba DA, Hayes S, Karl MO, Reh T
- Eye, retina, and visual system of the mouse. 2008. Chalupa L.M., Williams R.W. Cambridge, Mass.; MIT Press; ISBN: 9780262033817; Chapter 24: Specification, Histogenesis, and Photoreceptor Development in the Mouse Retina
Lamba D., Nelson B.R., Karl M.O. and T. Reh
- Neural regeneration and cell replacement: a view from the eye. Cell Stem Cell. 2008 Jun 5;2(6):538-49
Lamba D, Karl M, Reh T
- Stimulation of neural regeneration in the mouse retina. Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19508-13
Karl MO, Hayes S, Nelson BR, Tan K, Buckingham B, Reh TA
- (2009) Amacrine but not Bipolar Cells Regenerate in the Adult Murine Retina after NMDA Neurotoxic Damage. ARVO. IOVS. 50: E-Abstract 3062
Karl M.O., Hayes S, Nelson B.R., Tan K., Buckingham B., Reh T.A.
